Decreased In

Decreased In

• Secondary hypogonadism
• Kallmann's syndrome (inherited autosomal isolated deficiency of hypothalamic gonadotropin-releasing hormone; occurs in both sexes): Found in ~5% of patients with primary amenorrhea. Causes failure of both gametogenic function and sex steroid production (LH and FSH are "normal" or undetectable but rise in response to prolonged gonadotropin-releasing hormone stimulation).
• Pituitary LH or FSH deficiency.
• Gonadotropin deficiency.

Müllerian Inhibiting Substance, Serum

(Gonadal hormone produced by prepubertal testes to 919p1523j promote involution of müllerian ducts during normal male sexual differentiation. Detectable in normal boys from birth to puberty, when concentration declines.)

Use

• Differentiate anorchia from nonpalpable undescended testes in boys with bilateral cryptorchidism.
• Presence indicates testicular integrity in children with intersexual anomalies.
• Supplements or replaces measurement of response of serum testosterone to administration of hCG for gonadal evaluation in prepubertal children.

Decreased or Absent In

• Anorchia
• Negligible concentration in girls until puberty
• Female pseudohermaphroditism

Interpretation

• In prepubertal children, normal value in boys is sensitive and specific test predictive of testicular tissue (98%) and undetectable value predicts anorchia or ovaries (89%).
• Values are better than those for serum testosterone alone; combined with serum testosterone, sensitivity = 62% and specificity = 100% for absence of testes.23

Progesterone, Serum

Increased In

• Luteal phase of menstrual cycle
• Luteal cysts of ovary

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• Ovarian tumors (e.g., arrhenoblastoma)
• Adrenal tumors

Decreased In

• Amenorrhea
• Threatened abortion (some patients)
• Fetal death
• Toxemia of pregnancy
• Gonadal agenesis

17-Hydroxycorticosteroids (17-Ohks), Urine

(Derived from cortisol and cortisone. Measure approximately one-half to two-thirds of cortisol and its metabolites.)

Use

• Evaluation of adrenocortical function
• Screening and diagnostic test of glucocorticoid hypo- or hypersecretory disorders. Often replaced by measurement of urine free cortisol or serum cortisol, which it parallels.

Increased In

• Cushing's syndrome
• Adrenal tumors
• Marked stress (e.g., burns, surgery, infections)
• Use of certain drugs (e.g., acetazolamide, chloral hydrate, chlordiazepoxide, chlorpromazine, colchicine, erythromycin, estrogens, etryptamine, glucocorticoids, meprobamate, oleandomycin, paraldehyde, quinine and quinidine, spironolactone)

Decreased In

• Addison's disease
• ACTH deficiency
• Hypothyroidism
• Fasting
• Use of certain drugs (e.g., high-potency steroids [dexamethasone], narcotics, oral contraceptives, phenothiazines, phenytoin, reserpine)

17-Ketogenic Steroids (17-Kgs) (Corticosteroids), Blood and Urine

Use

• Evaluation of excessive or deficient glucocorticoid secretion
• Evaluation of 21-hydroxylase deficiency type of CAH
• Increasingly supplanted by measurements of serum cortisol, urine free cortisol, serum 17-hydroxyprogesterone, urine pregnanetriol

Increased In

• Adrenal hyperplasia
• Adrenal adenoma
• Adrenal carcinoma
• ACTH therapy
• Stress
• Other conditions (e.g., obesity, smoking)
• Use of certain drugs (e.g., glucocorticoids, ampicillin)

Decreased In

• Addison's disease
• Panhypopituitarism

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• Cessation of corticosteroid therapy
• General wasting disease
• Use of certain drugs (e.g., estrogens and oral contraceptives, dexamethasone)

17-Ketosteroids (17-Ks), Urine

(Metabolites of adrenal and gonadal androgenic steroids)

Use

• Indication of adrenal rather than testicular status; two-thirds are of adrenal origin in men; almost all are of adrenal origin in women.
• Diagnosis of ovarian and adrenal tumors. Supplanted by more specific RIA of DHEA and DHEA-S.
• May show daily variation of 100% in same individual

Increased In

• Interstitial cell tumor of testicle
• Virilizing ovarian tumors (e.g., adrenal rest tumor, granulosa cell tumor, hilar cell tumor, Brenner tumor, and, most frequently, arrhenoblastoma); increased in 50% of patients and normal in 50% of patients
• Adrenocortical hyperplasia (causing Cushing's syndrome, adrenogenital syndrome, precocious puberty)
• Adrenocortical adenoma or carcinoma
• Severe stress (e.g., burns, surgery, infections); exercise
• Pituitary tumor or hyperplasia
• ACTH or testosterone administration
• Third trimester of pregnancy
• Nonspecific chromogens in urine
• Use of certain drugs (e.g., ampicillin, cephaloridine, cephalothin, chloramphenicol, chlorpromazine, cloxacillin, danazol, dexamethasone, erythromycin, ethinamate, nalidixic acid, oleandomycin, penicillin, phenaglycodol, phenazopyridine, phenothiazines, quinidine, secobarbital, spironolactone)

Decreased In

• Primary hypogonadism (e.g., primary ovarian agenesis)
• Secondary hypogonadism
• Addison's disease
• Panhypopituitarism
• Nephrosis
• Generalized wasting disease
• Use of certain drugs (e.g., chlordiazepoxide, estrogens and oral contraceptives, metyrapone, opiates, phenytoin, probenecid, promazine, reserpine)

Testicle, Biopsy

Use

• Infertility workup
• Diagnosis of tumor

Interpretation

Normal spermatogenesis and normal endocrine findings in patient with aspermia and infertility suggests a mechanical obstruction to sperm transport that may be correctable.

Testosterone, Free, Plasma

Use

Evaluation of gonadal hormonal function

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Decreased In (Men)

• Primary hypogonadism (e.g., orchiectomy)
• Secondary hypogonadism (e.g., hypopituitarism)
• Testicular feminization
• Klinefelter's syndrome levels lower than in normal male but higher than in normal female and orchiectomized male
• Estrogen therapy
• Total testosterone decreased due to decreased sex hormone-binding globulin (e.g., cirrhosis, chronic renal disease)

Increased In

• Adrenal virilizing tumor causing premature puberty in boys or masculinization in women
• CAH
• Idiopathic hirsutism-inconclusive
• Stein-Leventhal syndrome-variable; increased when virilization is present.
• Ovarian stromal hyperthecosis
• Drugs that alter T -binding globulins may also affect testosterone-binding globulins; however, free testosterone level is not affected.

Gonadal Disorders

Ambiguous Genitalia

(Sexual ambiguity occurs in 1 in 1000 live-born infants.)

Females24

Condition Laboratory Finding CAH with or without salt losing Iatrogenic virilization No diagnostic test. History of maternal ingestion of virilizing agents (i.e., progestins). Maternal virilization Increased androgens in maternal serum Idiopathic virilization Normal plasma and urine steroids. 46 XX karyotype. Gonadal biopsy may show Leydig's tissue. Gonadal dysgenesis No specific laboratory test. Laparotomy usually shows a streak gonad on one side and testicular tissue on other side. Karyotype may be nondiagnostic (46 XX or 46 XY), multiple mosaic (44 XO/46 XX/47 XXY), or typical (45 XO/46 XY). True hermaphrodite No specific laboratory test. Biopsy of gonad shows ovarian follicles and testicular tubules. Karyotype may be 46 XX, 46 XY, or any mosaic included under gonadal dysgenesis. H-Y antigen is present.

Males24

Condition Laboratory Finding Absent müllerian inhibiting factor 46 XY karyotype. Normal steroid levels. No specific laboratory tests. Testes and uterii inguinali present. Undescended testes Normal gonadotropin and hormone levels. Anorchia May have low plasma testosterone and very high plasma FSH and LH. Later hCG stimulation is negative. Leydig's cell agenesis or hypoplasia Plasma testosterone is very low and fails to rise after hCG stimulation. High LD. Normal FSH. Biopsy of testicle is diagnostic.P.669 Unknown cause for unresponsiveness to androgens Karyotype 46 XY. Normal testosterone and dihydrotestosterone levels. No specific laboratory test. Faulty androgen action 46 XY karyotype. Normal testosterone level. Sex-linked defect type is diagnosed by in vitro binding study. LH may be high. Dihydrotestosterone level is normal. Autosomal recessive type has normal LH and FSH levels. Dihydrotestosterone level is low. Abnormal testosterone synthesis, no salt loss Increased 17-KS in urine and low plasma testosterone in one type. Decreased 17-KS in urine in other types. Abnormal testosterone synthesis, with salt loss Decreased 17-KS in one type. Increased plasma pregnenolone in other type. Hypopituitarism Decreased GH levels. Other tropic hormones may be deficient. Neonatal hypoglycemia is usual. Microphallus No specific laboratory test. Congenital malformations No specific laboratory test.

Laboratory Differential Diagnosis

Gonads Palpable

• Buccal smear chromatin positive and 17-KS normal
• True hermaphroditism
• Klinefelter's syndrome variant
• Buccal smear chromatin negative and 17-KS normal
• True hermaphroditism
• Anatomic defect
• Inherited enzyme deficiency syndrome affecting testosterone synthesis, metabolism, or action on target tissues
• Buccal smear chromatin negative and 17-KS increased
• CAH (3-beta-hydroxysteroid dehydrogenase deficiency)

Gonads Not Palpable

• Buccal smear chromatin positive and 17-KS normal
• True hermaphroditism
• Ovarian tumor (maternal 17-KS increased)
• Maternal exposure to androgens (history)
• Buccal smear chromatin positive and 17-KS increased
• CAH
• 11-beta-hydroxylase deficiency
• 21-hydroxylase deficiency
• 3-beta-hydroxysteroid dehydrogenase deficiency
• Buccal smear chromatin negative and 17-KS normal
• True hermaphroditism
• Gonadal dysgenesis (45 X/46 XY, 46 XY)

Precautions in Workup of Neonate with Ambiguous Genitalia

• Buccal mucosal smear for nuclear sex chromatin determination may show false-negative patterns during first 2 days of life so all chromatin-negative smears should be repeated after the third day. Sex chromatin in >25% of cells from the buccal mucosa indicates presence of at least two X chromosomes. A leukocyte culture for karyotype preparation should begin immediately whenever possible to confirm the sex chromosome constitution. The Y chromosome fluorescence test may also be valuable.
• A chromatin-positive newborn is almost always female.
• External genitalia are normal in Klinefelter's and most cases of Turner's syndrome

Amenorrhea/Delayed Menarche (Primary)

See Fig. 13-21.

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Due To

• Gonadal disorders (60% of all causes)
• Gonadal dysgenesis (75% of gonadal disorders)
• Testicular feminization syndrome (most common form of male hermaphroditism; female phenotype with male 46 XY karyotype, testosterone in male range; testes are present)
• Polycystic ovaries
• Resistant-ovary syndrome
• Structural genital tract disorders (35-40% of all causes)
• Imperforate hymen
• Uterine agenesis
• Vaginal agenesis
• Transverse vaginal septum
• Pituitary disorders (rare)
• Hypopituitarism
• Adenomas (prolactin secreting)
• Hypothalamic disorders (rare)
• Anatomic lesions (e.g., craniopharyngioma)
• Functional disturbance of hypothalamic-pituitary axis (e.g., anorexia nervosa, emotional stress)
• Systemic disorders
• Hypothyroidism
• CAH
• Debilitating chronic diseases (e.g., malnutrition, congenital heart disease, renal failure, collagen diseases)

Hormone Profiles

• Normal LH, FSH, prolactin, estradiol, testosterone, T , and TSH (eugonadal)
• Drugs
• Diet, anorexia
• Exercise
• Stress, illness
• Structural genital tract disorders (see previous section)
• Increased LH and normal FSH
• Early pregnancy
• Polycystic ovarian disease (Stein-Leventhal syndrome)
• Ectopic gonadotropin production by neoplasm (e.g., lung, GI tract)
• Increased LH and FSH (>30 mIU/mL), decreased estrogen (<50 pg/mL)
• Primary ovarian hypofunction
• Normal or low LH and FSH, decreased estrogen
• Hyperprolactinemia
• Isolated gonadotropin deficiency due to pituitary or hypothalamic impairment.
• Administer clomiphene citrate for 5-10 days; if gonadotropin level increases or menses return, cause is probably hypothalamic.
• Administer hypothalamic LH-releasing factor; normal or exaggerated response in hypothalamic amenorrhea (cause in 80% of patients); smaller or no response in pituitary tumor or dysfunction.
• Increased androgen
• Polycystic ovarian disease (testosterone level usually <200 ng/dL)
• Tumor of adrenal or ovary (testosterone level may be >200 ng/dL)
• Testicular feminization
• Use of anabolic steroids (e.g., in athletes)

Androgen Abuse

• (By athletes who use synthetic androgens to enhance performance or body building; effects depend on type and dose of drug used.)
• When exogenous testosterone is used, urine testosterone/epitestosterone ratio >6:1 is often considered indicative of steroid abuse (normal ratio is ~1:1 in men and women)
• Synthetic androgen or its metabolites are identified in urine.
• Erythrocytosis may occur.

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• Serum testosterone may be low.
• Decreased or normal LH and FSH
• Plasma HDL may be decreased and LDL may be increased.
• Platelet counts and platelet aggregation may be increased.
• Laboratory findings due to infertility and testicular atrophy

Androgen Deficiency (Hypogonadism)

See Tables 13-23 and .

Due To

• Secondary hypogonadism (hypogonadotropic)
• Secondary to pituitary-hypothalamic disorders
• Hyperprolactinemia
• Panhypopituitarism (pituitary or hypothalamus)
• Tumor
• Granulomatous disease
• Hemochromatosis
• Trauma
• Infarction, vasculitis
• Isolated gonadotropin deficiency
• Isolated FSH or LH deficiency
• Idiopathic hypothalamic hypogonadism
• Kallmann's syndrome
• Genetic disorders (e.g., Prader-Willi, Laurence-Moon-Biedl syndromes)
• Systemic (e.g., chronic disease, nutritional deficiency, massive obesity)
• Drugs (e.g., glucocorticoids)
• Constitutional (delayed puberty)

• Decreased serum testosterone (<100 ng/dL) with low or normal LH and FSH
• Decreased gonadotropin-releasing hormone
• Administration of gonadotropin-releasing hormone increases serum gonadotropin, testosterone, FSH, and LH

• Primary hypogonadism (hypergonadotropic)
• Gonadal
• Genetic
• Klinefelter's syndrome
• True hermaphroditism
• Defects in synthesis of androgens due to deficiency of various enzymes (e.g., 20-alpha-hydroxylase, 17,20-desmolase, etc.)
• Agenesis of testicles
• Miscellaneous (e.g., Noonan's syndrome, streak gonads, myotonia dystrophica, cystic fibrosis)
• Acquired (e.g., chemotherapy, irradiation, castration, drugs, alcohol, viral orchitis [especially mumps], cryptorchidism, chronic liver or kidney disease)
• Hormonal
• Hormonal insensitivity (e.g., androgen or LH insensitivity)
• Defects in action of androgens (pseudohermaphroditism)
• Complete (testicular feminization)
• Incomplete
• Type I (defects in testosterone receptors)
• Type II (5-alpha-reductase deficiency)

Climacteric, Male

• ○ Decreased testosterone level in blood (<300 ng/mL) and urine (<100 µg/24 hrs)
• ○ Urinary gonadotropin level is elevated. (Gonadotropin is decreased when low testosterone level is due to pituitary tumor, gout, or diabetes.)

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Corpus Luteum Deficiency

(Corpus luteum produces insufficient progesterone for development of endometrium receptive for pregnancy.)

Due To

• Any condition that interferes with follicle growth and development
• Severe systemic illness including liver, kidney, or heart dysfunction
• Hyperprolactinemia
• X-chromosome abnormalities
• Polycystic ovarian disease or other causes of inadequate FSH level early in cycle
• Deficient LH receptors on corpus luteum cells
• Inadequate LH level or deficient ovulatory surge
• Findings of endometrial biopsy on 26th day of cycle show less development than those of biopsy on menstrual day.
• Serum progesterone measured on three different days during midluteal phase totals <15 ng/mL and random level is <5 ng/mL.

Germinal Aplasia

• Biopsy of testicle shows that Sertoli's and Leydig's cells are intact and germinal cells are absent.
• ○ Azoospermia
• ○ Buccal smears are normal (negative for Barr bodies).
• ○ Chromosomal pattern is normal.
• Urinary gonadotropin is normal.
• Urinary pituitary gonadotropin is increased.
• 17-KS is decreased.

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Gynecomastia

See Fig. 13-23.

Due To

• Neonatality
• Puberty (25%)
• Drugs (10-20%) (e.g., spironolactone, estrogens, cimetidine)
• Cirrhosis or malnutrition (8%)
• Testicular tumors (3%) (e.g., Leydig's cell, Sertoli's cell, germ cell tumors containing trophoblastic tissue)
• Ectopic production of hCG by tumors (e.g., lung, liver, kidney)
• Primary gonadism (8%)
• Secondary gonadism (2%)
• Hyperthyroidism (1.5%)
• Renal disease (1%)
• Klinefelter's syndrome
• Feminizing adrenal cortical tumors
• Idiopathic (25%)
• Conditions usually associated with ambiguous genitalia or deficient virilization
• Androgen-insensitivity syndromes
• True hermaphroditism
• Enzymatic defects of testosterone production

Hirsutism

See Fig. 13-24.

Due To

• Ovarian
• Polycystic ovary syndrome
• Hyperthecosis syndrome
• Tumors (e.g., arrhenoblastoma, gonadoblastoma, dysgerminoma; Brenner cell, granulosa-theca cell, lipoid cell tumors)
• Adrenal
• Adenoma, carcinoma
• Cushing's syndrome
• CAH (21-hydroxylase deficiency, 11-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency)
• Drugs (e.g., anabolic steroids, androgens)
• Idiopathic (e.g., increased 5-alpha-reductase activity)

Infertility

• See Figs. 13-22, and .
• 85% of couples conceive after 12 mos of unprotected intercourse.
• Remaining 15% warrant investigation for infertility.

Due To

• Male factors (identified in ~40% of couples) (see Fig. 13-25)
• Testicular abnormalities (e.g., cryptorchidism, torsion, trauma, infection, varicocele)
• Coital factors (e.g., impotence)
• Toxins (e.g., anabolic steroids, marijuana, alcohol, medications [cyclosporine, spironolactone, cimetidine, nitrofurantoin])
• Others, e.g.,
• Sperm antibodies (numerous assay methods)
• Clinical significance of serum antibodies in men and women is controversial.
• Present in 10% of infertile men
• Present in infertile women in cervical mucus in 25% and in serum in 13%
• Irradiation

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P.677

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• Hyperthermia
• Heavy metals, e.g., lead, cadmium, manganese
• Pesticides
• Hypothalamic/pituitary disorders (e.g., hyperprolactinemia, deficiency of gonadotropin-releasing hormone)
• Chromosome abnormalities (e.g., Klinefelter's syndrome, Down syndrome)
• Female factors (identified in ~40% of couples) (see Fig. 13-22)
• Uterine factors
• Cervical (e.g., decreased cervical mucus quality or quantity, sperm antibodies)
• Uterine (e.g., endometriosis)
• Tube (e.g., salpingitis)
• Hypothalamic/pituitary disorders (e.g., hyperprolactinemia)
• Disorders of ovulation (e.g., polycystic ovaries)
• Chromosome abnormalities (e.g., Turner's syndrome)
• Others (e.g., irradiation)
• Combined male and female or unidentified factors in 20%.

Semen Analysis25, ,

• Use
• Infertility studies
• Absence of sperm to confirm vasectomy
• DNA test to confirm rape assailant

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P.680

• Reference Ranges

Volume >2 mL pH Color Translucent, gray-white, or opalescent Liquefaction <30 mins Viability >65% Motility >50% viable sperm with forward progression Progressive motility 3+ to 4+ Sperm density (count) >20 million/mL Morphology >30% normal forms Total motile functional sperm (= volume × % motility × sperm density × % normal morphology) >40 million RBCs 0-5/HPF WBCs 0-5/HPF (<10 /mL) Crystals None Clumping None Mixed antiglobulin reaction Negative Bovine cervical mucus penetration >30 mm Cultures for bacteria (Ureaplasma, Chlamydia) No pathogens Antisperm antibodies Negative

• Sterile males usually show
• Volume of <3 mL
• <20 million sperm/mL; only a count <5 million sperm/mL seems to reduce chance for pregnancy
• <25% motility
• Abnormal motility or morphology can occur with normal sperm counts but are usually seen with decreased counts. Abnormal forms indicate impaired spermatogenesis. Decreased motility may reflect defects in cilia structure elsewhere (in respiratory and reproductive tracts). Agglutination may indicate antisperm antibodies (which can be measured but relationship to infertility is not established).
• Normal morphology is >60% normal oval forms, <6% tapered forms, <0.5% immature forms, <8% amorphous forms. Tapered forms and spermatids are often increased in infertility associated with varicocele.
• Inflammatory cells may indicate infection of GU tract.
• Absent fructose (normally produced by seminal vesicles) may indicate absence or obstruction of vas deferens and seminal vesicles. Azoospermia, normal semen fructose, and normal serum FSH suggest obstruction proximal to entry of ejaculatory ducts.
• Large numbers of sperm in postejaculation urine in these patients suggests retrograde ejaculation.
• Repeated semen analysis (specimens collected 7 days apart) are necessary to characterize average spermatogenesis.
• Specimens should not be collected within 24 hrs of, or >5-7 days later than, previous ejaculation. Should be received in laboratory within 1 hr.
• ≤40% variability between different semen samples
• Comparison of split ejaculate specimens is useful in patients with abnormal semen analysis associated with a high volume; specimens may show marked differences.
• Antisperm antibodies (may test male serum or seminal fluid or female serum or cervical mucus) may occur in
• Testicular trauma (even minor)
• Almost all vasectomized patients
• Viral orchitis (permanent)
• Bacterial infections of GU tract (usually transient)
• Cervical mucus penetration test measures greatest distance traveled by an individual sperm from a small aliquot of semen incubated 90 mins in a capillary tube of bovine cervical mucus. 68% of infertile men had penetration scores <20 mm whereas 79% of fertile men had scores >30 mm.
• Hamster egg penetration assay: hamster oocytes enzymatically treated to remove outer layers of egg (which prevent cross-species fertilization) are incubated with human sperm selected for their motile ability. Penetration rates of <15% (number of eggs penetrated) indicate reduced fertility. May also be reported as number of sperm penetrations

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per egg (normal = ≥5). Positive test results indicate ability of sperm to propel itself to oocyte, bind to oocyte, and penetrate oocyte.

• After vasectomy, spermatozoa are present for some time. To confirm efficacy, two centrifuged specimens properly collected 1 mo apart should be sperm free and fructose should be absent.

Klinefelter's Syndrome

• (Patients have 2 or more X chromosomes)
• Azoospermia
• Plasma LH and FSH are increased; high FSH is best demarcator between normal men and those with Klinefelter's syndrome.
• Urinary gonadotropin level is elevated.
• Plasma testosterone levels are decreased to normal.
• Buccal smears are helpful if positive for Barr bodies but a negative result does not rule out mosaicism. If negative, chromosome analysis should be performed, but in 70% of patients mosaic pattern may occur only in testes, so that chromosomal analysis of testicular cells is required for definite diagnosis.
• Abnormal chromosomal pattern. XY males have an extra X; 47 XXY is the classic type; 10% of patients have the mosaic form (46 XY/47 XXY); may have additional X (e.g., XXXY, XXXXY).
• Biopsy of testicle shows atrophy, with hyalinized tubules lined only by Sertoli's cells, clumped Leydig's cells, and absent spermatogenesis.
• Laboratory findings due to associated conditions, e.g., breast cancer, diabetes mellitus, thyroid dysfunction.

Menopause (Female Climacteric)

• Serum estradiol <5 ng/dL and FSH >40 mU/mL confirms primary ovarian failure; progesterone is <0.5 ng/mL.
• Urinary estrogens are decreased.
• Urinary 17-KS are decreased.
• Plasma and urinary gonadotropin are increased.
• Vaginal cytology shows menopausal pattern.

Ovarian Insufficiency, Secondary

Due To

• Deficient estrogen production, e.g., diseases of the pituitary or hypothalamus (see separate sections)
• Normal or increased estrogen production, e.g., ovarian tumors, functional cysts of ovary that suppress LH and FSH secretion
• Disorders of adrenal function (increased production of cortisol or androgens) or thyroid function.

• Urinary gonadotropin is decreased or absent
• Plasma LH is <0.5 mU/mL.

Ovarian Tumors

Feminizing Ovarian Tumors

• (E.g., granulosa cell tumor, thecoma, luteoma)
• ○ Pap smear of vagina and endometrial biopsy show high estrogen effect and no progestational activity; no signs of ovulation during reproductive phase.
• ○ Urinary FSH is decreased (inhibited by increased estrogen).
• Urine 17-KS and 17-OHKS are normal.
• ○ Pregnanediol is absent.

Masculinizing Ovarian Tumors

• (E.g., arrhenoblastoma, hilar cell tumors, adrenal rest tumors)
• Androgen-secreting tumor of ovary or adrenal gland is highly likely if serum total testosterone is >200 ng/dL or DHEA-S is >800 µg/dL. Localization may require androgen measurement in blood from adrenal and ovarian veins.

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• ○ Pap smear of vagina shows decreased estrogen effect.
• ○ Endometrial biopsy shows moderate atrophy of endometrium.
• Urine FSH (gonadotropins) is low.
• Urine 17-KS level is normal or may be slightly increased in arrhenoblastoma. Level may be markedly increased in adrenal tumors of ovary ("masculinovoblastoma"). The higher the urine 17-KS level, the greater the likelihood of adrenocortical carcinoma; value of >100 mg/24 hrs is virtually diagnostic. Level may be moderately increased in Leydig's cell tumors.
• In arrhenoblastoma an increased amount of androsterone, testosterone, etc., may be excreted in urine even though the 17-KS level is not much increased. Normal or slightly increased urine 17-KS level in association with plasma testosterone in male range is almost certainly due to ovarian tumor.
• In adrenal cell tumors of ovary, laboratory findings may be the same as in hyperfunction of adrenal cortex with Cushing's syndrome, etc
• In some cases no endocrine effects are seen from these tumors. Some cases of arrhenoblastoma with masculinization also show evidence of increased estrogen formation

Struma Ovarii

~5-10% of cases are hormone producing. Classic findings of hyperthyroidism may occur. These tumors take up radioactive iodine. (Simple follicle cysts may also take up radioactive iodine.)

Primary Chorionepithelioma of Ovary

• Urinary chorionic gonadotropins are markedly increased
• Estrogen and progesterone secretion may be much increased.

Nonfunctioning Ovarian Tumors

Only effect may be hypogonadism due to replacement of functioning ovarian parenchyma.

Tumor Markers

• Serum CA-125 is useful for
• Postoperative monitoring for persistent or recurrent disease; poorer prognosis if elevated 3-6 wks after surgery. Lower levels in patients with no residual tumor or <2 cm of residual tumor. But a negative test does not exclude residual disease.
• Rising level during chemotherapy is associated with tumor progression and fall to normal is associated with response. Remains elevated in stable or progressive disease.
• Rising level may be indication for second-look operation even in presence of normal clinical examination. Specificity = 99%, sensitivity = 46%, positive predictive value = 97% for second-look cases.
• Higher levels are seen in less differentiated tumors (grade 2 and 3) and in serous cystadenocarcinoma. Not increased in mucinous adenocarcinoma.
• Sequential determinations are more useful than a single test because levels in benign disease do not show significant change but progressive rise occurs in malignant disease.
• Rising level may precede clinical evidence of recurrence by up to 11 mos.
• Not used for screening because it is negative in 20% of cases at time of diagnosis; normal level does not exclude tumor; greater elevation roughly related to poorer survival.
• CA-125 is positive in 80% of cases of common epithelial tumors, 50% of early-stage disease, 0.6% of healthy women older than age 50 yrs.
• Beta-hCG is positive in almost all cases of choriocarcinoma, 10-30% of cases of seminomas, and 5-35% of cases of dysgerminoma. See Trophoblastic Neoplasms section.
• AFP is present in 80-90% of cases of endodermal sinus tumors or immature teratomas.
• CEA is present in 50-70% of cases of serous carcinoma. CA-125/CEA ratio is much higher in serous carcinoma (>10 and often >100) than in carcinomas of breast, lung, colon, or pancreas (usually <10), which may also cause increased levels of these markers.

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Germ Cell Tumors of the Ovary

Tumor AFP hCG Seminoma Seminoma with syncytiotrophoblastic giant cells (STGC) Embryonal carcinoma Embryonal carcinoma with STGC Yolk sac tumor Yolk sac tumor with STGC Choriocarcinoma Mature teratoma See Chapter 16. When both markers are positive, both should be assayed after therapy, as recurrence or metastases may be reflected by increase of only one marker.

Stein-Leventhal Syndrome (Polycystic Ovarian Disease)

• Serum increased ~3× normal (>35 mU/mL) in ~60% of patients in association with normal or slightly low FSH level. Abnormally high LH/FSH ratio (>2) is more consistently abnormal than is either measurement alone. Ratio ≥ 2 is considered highly suggestive; ratio ≥ 3 is considered diagnostic.
• Increased serum LH, LH/FSH ratio of >2, and mild increase of ovarian androgen level are sufficient for diagnosis in presence of the symptoms and clinical signs. Because of erratic daily fluctuations of LH and androgens, obtaining daily plasma specimens for 3-5 days may be necessary.
• Plasma free testosterone is increased ≤200 µg/dL in 40-60% of cases (>200 µg/dL usually indicates an androgen-producing tumor); not suppressed by dexamethasone.
• Plasma androstenedione (DHEA) is increased in ≤50% of cases.
• Serum 3-alpha-androstanediol glucuronide (metabolite of dihydrotestosterone) is markedly increased in this and in idiopathic hirsutism.
• Synthetic estrogens and progestins (as in oral contraceptives) for 21 days, with before and after measurement of free testosterone and androstenedione:
• Free testosterone and androstenedione decrease by 50% or become normal in LH-dependent hyperandrogenism, e.g., polycystic ovaries.
• No suppression occurs in patients with ovarian tumors or adrenal disorders.
• Change in free testosterone accounts for estrogen-caused increase in sex hormone-binding globulin, which could result in unchanged or increased total testosterone level.
• ~85% of these patients have one or more abnormalities of serum LH/FSH ratio, testosterone, or androstenedione. Hyperandrogenism does not differentiate condition from CAH but CAH is more likely if LH/FSH ratio is <2:1 and ovaries are normal in size.
• Urinary 17-KS are somewhat increased (higher values occur in congenital virilizing adrenal hyperplasia and hyperadrenalism due to Cushing's syndrome). (Measurement of DHEA-S is preferable to evaluate adrenal disease.) Dexamethasone administration (0.5 mg four times a day for 5-7 days) causes partial suppression in cases of ovarian origin, but complete suppression suggests adrenal origin (e.g., late-onset CAH). Administration of gonadotropin increases urinary 17-KS.
• Biopsy of ovary is consistent with increased androgen effect but is not specific; ovarian visualization and biopsy are not routine part of diagnosis.
• Plasma cortisol, urinary 17-OHKS, and 17-KGS are normal.
• Plasma prolactin is increased in ~30% of patients.
• Hyperinsulinemia occurs for unknown reason; correlates with degree of increased androgens.
• 10-13% of these patients have partial 21-hydroxylase defects.
• ○ If testosterone is >2 ng/mL or DHEA is >7000 ng/mL, ovarian or adrenal tumor should be ruled out.
• Laboratory tests may be helpful in defining pathogenesis, following course of treatment, or ruling out adrenal or ovarian tumors.
• Increased serum LH with normal or decreased FSH may occur in simple obesity, hyperthyroidism, liver disease

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Testicular Tumors

Tumor Serum Tumor Marker Seminoma hCG increased in ~10% AFP not increased in pure seminoma without teratomatous component Embryonal carcinoma hCG or AFP or both increased in 90% Yolk sac tumor AFP increased in 100% Choriocarcinoma (pure) hCG increased in 100% Teratoma hCG or AFP or both increased in 50% Mixed tumor hCG and AFP increased in 90%

• Increased serum hCG (>1-2 ng/mL or >5-10 mU/mL) is found in 40-60% of patients with metastatic nonseminomatous tumors and in 15-20% of patients with apparently pure metastatic seminoma. In the latter case, immunochemical staining of paraffin-embedded tumor should be performed, because isolated syncytiotrophoblastic cells may show the hormone but are not by themselves evidence of choriocarcinoma.
• Increased serum AFP (>20 ng/mL) is found in ≤ 70% of patients with metastatic nonseminomatous tumors (embryonal carcinoma and yolk sac tumors).
• Both markers should always be measured simultaneously. 40% of patients with nonseminomatous tumors have increase of only one marker. 90% of patients with testicular tumors are positive for AFP or hCG or both; these are valuable for gauging efficacy of chemotherapy. 30% of patients receiving intensive chemotherapy apparently have a complete clinical remission; AFP levels may remain increased, although lower than pretreatment levels.
• 20-30% of patients have false-negative results preoperatively despite tumor (usually microscopic) in the retroperitoneal lymph nodes. Therefore, lymphadenectomy should not be omitted simply because marker levels are normal.
• Serum markers for AFP and beta-hCG may be increased in conditions other than testicular cancer. See Chapter 16. False-positive increase is rare.
• The most important use is for follow-up after surgery or chemotherapy. Failure of increased preoperative levels to fall after surgery suggests metastatic disease and the need for chemotherapy. Rise of levels that had previously declined to normal suggests recurrent tumor even with no other evidence of disease. Serum half-life of AFP = 5-7 days and of hCG = 30 hrs.
• Negative marker findings are not useful for differential diagnosis of scrotal mass, but elevated levels indicate testicular cancer.
• Serum LD is a third marker; not specific for testicular cancer but also appears to be an independent prognostic factor for advanced germ cell tumors. Increased in ~60% of nonseminomatous germ cell tumors and 80% of seminomatous germ cell tumors.

Turner's Syndrome (Ovarian Dysgenesis)

• Diagnosis is based on karyotype analysis. Chromosomal pattern includes wide spectrum of abnormalities, e.g., 45 chromosomes (monosomy X with XO; or, if XX, one X is abnormal; or XO mosaic), various deletions of part of an X chromosome. Female is phenotypic. Prenatal diagnosis by chorionic villus sampling or amniocentesis.
• Barr body test is negative (male) in 80% of patients.
• Because of the frequency with which 45 X cells are admixed with 46 XX cells, the diagnosis (i.e., 45 X karyotype) cannot be excluded by either buccal smear or chromosome analysis alone.
• Biopsy of ovary shows connective tissue stroma with rare follicular structure.
• Vaginal smear and endometrial biopsy are atrophic.
• Increased FSH, LH, and gonadotropins.
• 17-KS and 17-OHKS are normal.
• ACTH is normal.
• Glucose intolerance is common, with mild insulin resistance.
• Serum cholesterol is frequently increased.
• Laboratory findings due to increased prevalence of associated conditions, e.g.,
• Hashimoto's thyroiditis (10-30%)
• Bicuspid aortic valves (≤ 50%)
• Coarctation of aorta (≤ 20%)

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• Horseshoe kidneys
• Pyelonephritis due to anomalous obstruction of ureteropelvic junction
• Hypertension
• Frequent otitis media
• ~60% of patients with primary amenorrhea have Turner's syndrome or sometimes testicular feminization. 90% never menstruate. ~10% menstruate for a few years and then present as cases of secondary amenorrhea.

Turner's Syndrome in the Male

• Biopsy of testicle reveals dysgenetic tubules with few or no germ cells.
• Chromosomal pattern: 46 chromosomes (XY pattern with very defective Y that is equivalent to XO).

Laboratory Tests for Diagnosis of Disorders of the Pituitary and Hypothalamus

Arginine Vasopressin (Antidiuretic Hormone [Adh])

Use

• Diagnosis of central diabetes insipidus and of SIADH, and differentiation from nephrogenic diabetes insipidus
• Differential diagnosis of hyponatremias

Increased in Serum

• SIADH (inappropriately increased for degree of plasma osmolality)
• Ectopic ADH syndrome
• Use of certain drugs (e.g., chlorpropamide, phenothiazine, carbamazepine [Tegretol])
• Nephrogenic diabetes insipidus (normal for degree of plasma osmolality)

Decreased in Serum

Central diabetes insipidus

In Urine

• Central diabetes insipidus: low arginine vasopressin and osmolality
• Nephrogenic diabetes insipidus: high arginine vasopressin and low osmolality
• SIADH: normal arginine vasopressin relative to osmolality

Growth Hormone (Gh)

Use

• Differential diagnosis of short stature, slow growth
• Evaluation of pituitary function

Increased In

• Acromegaly and gigantism due to certain pituitary adenomas
• Laron dwarfism (GH resistance; GH-binding protein cannot be detected)
• Renal failure
• Uncontrolled diabetes mellitus
• Use of certain drugs (e.g., estrogens, oral contraceptives, tranquilizers, antidepressants)
• Starvation
• 2 hrs after sleep

Decreased In

• Hypothalamic defect causes most cases (e.g., tumors, infection, diseases such as hemochromatosis, perinatal insult such as birth trauma)

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• Hypopituitarism (e.g., familial isolated GH deficiency, tumors, infection, granulomas, trauma, irradiation)
• Dwarfism
• Corticosteroid therapy
• Obesity
• Low levels must be measured after stimulation (e.g., with insulin, arginine)

Growth Hormone-Releasing Hormone

(Hypothalamic secretion stimulates pituitary to release GH)

Increased In

1% of cases of acromegaly due to production of GH-releasing hormone by hypothalamus or ectopic secretion by neoplasms (e.g., pancreatic islet, carcinoid of thymus or bronchus, neuroendocrine tumors)

Normal In

Most cases of acromegaly due to pituitary tumors.

Prolactin

See Prolactinoma.

Somatomedin C

(Insulin-like growth factor I, which mediates most growth-promoting effects of GH)

Use

• Diagnosis of acromegaly and pituitary deficiency; preferable to GH because it is constant after eating and during the day
• Screening of other growth disorders
• Assessment of nutritional status
• Monitoring of effectiveness of nutritional repletion. Is more sensitive indicator than prealbumin, transferrin index, or retinol-binding protein.

Increased In

• Acromegaly and gigantism
• Pregnancy (2-3× nonpregnancy values)

Decreased In

• Pituitary deficiency
• Laron dwarfism
• Anorexia or malnutrition
• Acute illness
• Hepatic failure
• Hypothyroidism
• Diabetes mellitus
• Normal aging

Diseases of the Pituitary and Hypothalamus

Acromegaly and Gigantism

• Serum somatomedin C (insulin-like growth factor I) is uniformly increased in untreated cases; is more precise and cost-effective screening than serum GH because GH levels fluctuate and have short serum half-life (22 mins).
• Autonomous serum GH is increased. (Avoid stress before and during venipuncture because stress stimulates secretion of GH; several random measurements should be performed.) Annual random blood GH levels, FTI, and ACTH are used for treatment follow-up.

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• Fasting levels >5 ng/mL in men or >10 ng/mL in women are suggestive but not diagnostic of acromegaly.
• Most patients show a fall of <50% or even an increase 60-90 mins after glucose administration (50-100 gm orally), whereas normal subjects show almost complete suppression of GH (or to <5 ng/mL) by induced hyperglycemia. This is the most reliable test. Failure to suppress GH to <2 ng/mL after oral glucose load is essential to diagnosis.
• If borderline response to hyperglycemia, perform TRH test. (500 µg TRH IV causes transient increase [>50% over basal levels] of GH in 15-30 mins in acromegaly patients but has little effect in normal persons.)
• GH-releasing hormone excess secretion (e.g., ectopic source such as pancreatic tumor or carcinoid causes <1% of acromegaly cases). Thus GH-releasing hormone should be measured in all patients with acromegaly.
• All patients with acromegaly should have baseline serum prolactin measured because ≤ 40% of these adenomas may secrete both prolactin and GH.
• IV ACTH administration may cause excessive increase in urine 17-KS but normal 17-OHKS excretion.
• Glucose tolerance is impaired in most patients. Mild diabetes mellitus that is insulin resistant is found in <15% of patients.
• Adrenal virilism and increased urine 17-KS are common in women.
• Urine 17-KS, 17-KGS, and gonadotropins are usually normal or may be slightly changed but level not diagnostically useful.
• Hypogonadism develops in ≤ 50% of cases.
• Rare associated endocrinopathies are hyperthyroidism, HPT, pheochromocytoma, insulinoma.
• In inactive cases, all secondary laboratory findings may be normal.
• In late stage, panhypopituitarism may develop.
• Serum phosphorus is increased for age of patient in 40% of cases.
• Serum ALP may be increased.
• Urine calcium is increased.
• Urine hydroxyproline is increased.
• Biopsy of costochondral junction evidences active bone growth.
• CBC and ESR are normal.
• After successful surgery-basal plasma GH <5 ng/mL, should decrease to ≤2 ng/mL after glucose administration and level of insulin-like growth factor I should become normal.

Due To

• Excess GH secretion
• Pituitary adenomas, hyperplasia, or carcinoma
• Ectopic pituitary tumor (sphenoid or parapharyngeal sinus)
• Ectopic hormone production (e.g., tumor of pancreas, lung, ovary, breast)
• Excess secretion of GH-releasing hormone
• Hypothalamic tumor (e.g., hamartoma, ganglioneuroma)
• Ectopic hormone production (e.g., carcinoid of bronchus, GI tract, pancreas; pancreatic islet cell tumor, small cell carcinoma of lung, adrenal adenoma, pheochromocytoma)

Other Causes of Tall Stature in Children

• Klinefelter's syndrome
• Marfan syndrome (inherited disorder with thin limbs, malformation of eyes and ears, medionecrosis of aorta, cardiac valve deformities, hypotonia, kyphoscoliosis)
• Beckwith-Wiedemann syndrome (hypoglycemia, omphalocele, macrosomia, macroglossia)
• Untreated CAH
• Precocious secretion of androgens or estrogens
• Obesity

Anorexia Nervosa

• No diagnostic or typical laboratory profile; diagnosis by exclusion. Findings may be compensatory regulatory changes secondary to nutritional deprivation rather than primary hypothalamic dysfunction.
• ESR is low.
• Vomiting may cause hypokalemic acidosis.

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• Prerenal azotemia with increased BUN and serum creatinine
• Decreased serum glucose, sodium, magnesium
• Renal calculi
• Laboratory findings of euthyroid sick syndrome
• Basal GH levels may be increased as in other forms of protein-calorie malnutrition; response to stimulation tests is usually normal.
• Increased plasma somatomedin C
• Plasma prolactin level is normal.
• Plasma LH and FSH may be low with impaired response to LH-releasing hormone.
• Decreased serum estradiol
• Decreased serum testosterone
• Adrenal function abnormalities may be found (e.g., normal or increased plasma corticoids, absence of diurnal variation of glucocorticoids, hyperresponse to ACTH test, incomplete suppression by dexamethasone, intact or excessive response to metyrapone, low 17-KS and 17-KGS in urine; no adrenal insufficiency)
• Atrophic vaginal smear
• Increased serum carotene (>250 mg/dL) in ~60% of cases and increased cholesterol
• Anemia is unusual; leukopenia; thrombocytopenia.
• With marked loss of body weight, serum protein, potassium, and phosphorus may be decreased.
• Vitamin deficiencies are rare.

Carcinoid Syndrome

• See Table 13-25.
• (The syndrome in malignant carcinoids [argentaffinomas] includes flushing, diarrhea, bronchospasm, endocardial fibrosis, arthropathy, glucose intolerance, hypotension.)
• Liver metastases are present in 95% of cases with syndrome except when lung and ovary are primary sites, but laboratory tests are not reliable indicators and serum ALP is frequently normal despite extensive metastases.
• Urinary level of 5-HIAA (a metabolite of serotonin) is increased in 75% of cases (>9 mg/24 hrs in patients without malabsorption or >30 mg/24 hrs with malabsorption; normal is <6 mg/24 hrs), usually when tumor is far advanced (with large liver metastases often 300-1000 mg/day), but may not be increased despite massive metastases. Sensitivity = 73%. Useful in diagnosis in only 5-7% of patients with a carcinoid tumor but in ~45% of those with liver metastases. Disease extent and prognosis correlate generally with urine 5-HIAA excretion; becomes normal after successful surgery. If urine HIAA is normal, check blood level of serotonin or a precursor, 5-hydroxytryptophan. Urine HIAA may be decreased in renal insufficiency.

Increased In

• Whipple's disease
• Nontropical sprue
• Small increases may occur in pregnancy, ovulation, after surgical stress.
• Consumption of various foods (e.g., pineapples, kiwis, bananas, eggplants, plums, tomatoes, avocados, plantains, walnuts, pecans, hickory nuts, coffee)
• Use of certain drugs (e.g., acetanilid, acetaminophen, acetophenetidin, caffeine, glyceryl guaiacolate, heparin, L-dopa, mephenesin, methocarbamol, phenothiazine derivatives, Lugol's solution, reserpine, salicylates)

Decreased In

• Use of certain drugs (e.g., chlorpromazine, promazine, imipramine, isoniazid, monoamine oxydase inhibitors, methenamine, methyldopa, phenothiazines, promethazine)
• Serum and urine serotonin may be increased (>0.4 µg/mL) in 20% of cases but without increased urine 5-HIAA.
• Platelet serotonin and urine serotonin are increased in 64% of cases.
• Increased plasma chromogranin A predicts adverse prognosis.

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• Some tumors can produce various functionally active substances (e.g., histamine, ACTH, somatostatin, gastrin, catecholamines, prostaglandins, kinins) causing different paraneoplastic syndromes. Most are clinically silent because of small amounts secreted and rapid inactivation.
• VMA and catecholamine levels in urine are normal.
• Laboratory findings due to other aspects of carcinoid syndrome (may include pulmonary valvular stenosis, tricuspid valvular insufficiency, heart failure, liver metastases, electrolyte disturbances)
• Nonfunctioning tumors can be diagnosed only by histological examination.
• Some patients may have decreased serum albumin and pellagra (due to diversion of tryptophan to synthesis of serotonin).

Diabetes Insipidus

See Table 13-26.

Due To

• Central (pituitary)
• Nephrogenic
• Psychogenic
• High-set osmoreceptor

Diabetes Insipidus, Central

See Table 13-26.

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Due To

• Primary
• Idiopathic (now accounts for <50% of cases)
• Heredity (~1% of cases)
• Secondary
• Supra- and intrasellar tumors
• Neoplasms (suprasellar and intrasellar
• Primary (e.g., craniopharyngioma, cyst)
• Metastatic (e.g., carcinoma of breast, lung; leukemias)
• Histiocytosis (eosinophilic granuloma is most common)
• Hand-Schüller-Christian disease
• Granulomatous lesions (e.g., sarcoidosis, TB, syphilis, Wegener's granulomatosis)
• Trauma, with or without basal skull fracture; neurosurgical procedures
• Vascular lesions (e.g., aneurysms, thrombosis, sickle cell disease, Sheehan's syndrome
• Infections (e.g., meningitis, encephalitis, Guillain-Barré syndrome, CMV infection)
• Autoimmune disorders
• Others (e.g., hypoxemic encephalopathy)

• Urine is inappropriately dilute (low specific gravity [usually <1.005] and osmolality [50-200 mOsm/kg]) in presence of increased serum osmolality (295 mOsm/kg) and increased or normal serum sodium.
• Large urine volume (4-15 L/24 hrs) is characteristic.

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• Plasma vasopressin level is decreased
• Dehydration test fails to increase urine specific gravity or osmolality, and serum osmolality remains elevated. After administration of vasopressin, urine osmolality increases by 50%.
• Partial central diabetes insipidus shows intermediate values between complete central and normal.
• See Tables 13-26 and .

Diabetes Insipidus, Nephrogenic

See Table 13-26.

Due To

• Chronic renal failure (e.g., GN, pyelonephritis, gout, analgesic nephropathy, polycystic kidneys, nephrosclerosis)
• Other tubulointerstitial diseases (e.g., polycystic kidneys, medullary sponge disease, sickle cell disease or trait, amyloidosis)
• Diuretic phase of acute tubular necrosis
• After renal transplant or relief of urinary tract obstruction
• Hypergammaglobulinemia (e.g., multiple myeloma, amyloidosis, Sjögren's syndrome)
• Drugs (e.g., lithium, demeclocycline, amphotericin, propoxyphene, methoxyflurane, vincristine)
• Prolonged potassium depletion and hypokalemia (condition is reversed by restoring potassium level to normal)

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• Prolonged hypercalciuria, usually with hypercalcemia (condition is reversed by restoring calcium level to normal)
• Hereditary renal tubular unresponsiveness to vasopressin due to X-linked genetic defect; severe form occurs in males; family history of this condition is frequent.
• Primary hyperaldosteronism
• Pregnancy

• Laboratory findings are the same as in hypophyseal (central) diabetes insipidus except that in nephrogenic type
• Plasma vasopressin level is normal or increased.
• Dehydration test does not cause urine osmolality to increase above plasma osmolality.
• Dehydration test causes the plasma vasopressin level to increase.
• Urine osmolality does not increase with subsequent injection of vasopressin.

Diabetes Insipidus Due to High-Set Osmoreceptor

• (Rare entity in which the set point for stimulating release of ADH is ≥ 300 mOsm/kg instead of the normal 285 mOsm/kg level)
• See Table 13-26.
• As plasma osmolality increases, patient becomes thirsty and drinks fluids, thereby diluting the plasma before it reaches the higher set level to stimulate release of ADH, initiating cycle of polyuria and polydipsia. If thirst center is also impaired, patient develops essential hypernatremia.
• Plasma osmolality after dehydration is significantly higher than in normal state.
• Urine osmolality does not increase after administration of vasopressin.

Growth Hormone (GH) Deficiency

• May be isolated deficiency with dwarfism or may be associated with TSH deficiency, with ACTH deficiency, or with TSH and ACTH deficiencies. GH deficiency is usually due to deficiency of hypothalamic GH-releasing hormone.
• Serum GH basal levels are decreased (<1.0 ng/mL). Use pooled or average of three samples. Stimulation tests have greater sensitivity. Increased basal or random serum level excludes this diagnosis but low levels do not distinguish normal persons from those with GH deficiency.
• Stimulation (functional) tests
• Draw serum at 0, 30, 60, 90, and 120 mins.
• Administration of insulin (regular crystalline, IV, 0.05 to 0.3 U/kg body weight) should normally produce at least 2× increase in serum GH level and 3× increase in serum prolactin level at 60-min peak. This is the most reliable challenge for GH secretion.
• Administration of levodopa (500 mg orally) should normally produce at least 2× increase in serum GH level at 60-min peak.
• Administration of arginine (0.5 gm/kg body weight as 5% solution IV over 30 mins) should normally produce at least 3× increase in serum GH and at least 2× increase in serum prolactin level at 30- to 60-min peak.
• Failure to produce these minimal responses indicates a lesion of pituitary or hypothalamus but does not differentiate between them.
• A normal response is at least 10 ng/mL peak value; 5-10 ng/mL is indeterminate, ≤5 ng/mL is subnormal. (A normal value rules out GH deficiency; in some laboratories the normal level is ≥ 7 ng/mL.)
• Approximately one-fourth of patients with normal GH secretory capacity are unable to secrete GH in response to provocative tests indicated above, at any given time. Therefore, at least two of these tests should be used to confirm diagnosis of GH deficiency.
• Nonpituitary factors that impair GH response include obesity, primary hypothyroidism, thyrotoxicosis, primary hypogonadism, Kallmann's syndrome, Cushing's syndrome, use of various drugs (e.g., alpha-adrenergic antagonists, beta-adrenergic antagonists, serotonin antagonists, dopamine antagonists). Impaired GH response may even occur in presence of elevated GH basal level.

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• Normal response may also occur in patients with partial deficiency.
• GH response is normal or exaggerated in growth failure due to resistance to GH (Laron dwarfism) or resistance to somatomedins (African pygmies).
• Glucagon and clonidine have also been used.
• Decreased fasting blood sugar (<50 mg/dL) is frequent; responds to GH therapy. Serum phosphorus and ALP are decreased in prepubertal children but normal in adult-onset cases.
• Serum prolactin baseline level is low and does not rise appropriately after TRH administration or other stimulation. In hypothalamic disease, basal prolactin level is increased and response may be normal or blunted.
• Laboratory findings due to involvement of other endocrines
• TSH deficiency (see Sensitive Thyroid-Stimulating Hormone; TRH stimulation test, Hypothyroidism, and Table 14-3).
• ACTH deficiency (see tests of adrenal function).
• Gonadotropins are decreased or absent from urine in postpubertal patients (but increased levels occur in primary hypogonadism).

Hypernatremia, "Essential"

• (Due to hypothalamic lesions [e.g., infiltration of histiocytes, neoplasm] that cause impaired osmotic regulation but intact volume regulation of ADH secretion.)
• See Fig. 13-27.
• Serum sodium shows sustained but fluctuating elevations, corrected by administration of ADH but not corrected by fluid administration.
• Serum osmolality is increased
• Serum creatinine, BUN, and creatinine clearance are normal.
• There is spontaneous excretion of random specimens of urine, which may be very concentrated or very dilute and opposite to plasma osmolality.

Hyponatremias

See Table 13-27 and Fig. 13-28.

Due To

• Isotonic (spurious-occurs with flame photometer but not with ion-selective electrode technology)
• Hyperlipidemia (plasma looks milky) "falsely" lowers serum sodium; measured serum osmolality exceeds calculated serum osmolality.
• Calculated serum osmolality = 2 × Na + (serum glucose/18) + (BUN/2.8)
• Hyperproteinemia (e.g., myeloma, macroglobulinemia)
• Hypertonic
• Hyperglycemia (each increase of blood sugar of 100 mg/dL decreases serum sodium by 1.7 mEq/L)
• Excess mannitol treatment
• Hypotonic
• Hypervolemic, usually with clinical edema
• With low urine sodium (<10 mEq/L) may be due to congestive heart failure, cirrhosis with ascites, nephrotic syndrome
• With high urine sodium (>20 mEq/L) may be due to acute tubular necrosis or end-stage chronic renal failure in which sodium and water intake exceeds excretion. Serum uric acid and BUN tend to be increased.
• Hypovolemic
• Urine sodium <10 mEq/L. Due to extrarenal loss of sodium (e.g., GI tract, fistulas, pancreatitis, exercise, sweating, burns).
• Urine sodium >20 mEq/L. Due to renal loss of sodium (e.g., diuretics such as furosemide or osmotic diuresis due to glucose or urea, diabetic ketoacidosis, renal tubular acidosis, salt-losing nephritis, adrenal insufficiency, hyporeninemia, hypoaldosteronism).
• Normovolemic-usually no edema is present.

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• Large amounts of sodium appear in urine (>20 mEq/L). May be due to SIADH, hypothyroidism, hypopituitarism, low-reset osmostat syndrome, physical or emotional stress, potassium depletion, renal failure, water poisoning, certain drugs (e.g., ADH analogs, amitriptyline, carbamazepine, chlorpropamide, cyclophosphamide, diuretics, haloperidol, thioridazine, vincristine).
• Hyponatremic patients with BUN <10 mg/dL and uric acid <3.0 mg/dL should be considered to have SIADH or reset osmostat until proved otherwise
• "Pseudohyponatremia"-see above. Serum osmolality is normal.

Hypopituitarism

Due To

• Pituitary disease
• Neoplasms (e.g., craniopharyngioma, chromophobe adenoma, eosinophilic adenoma, meningioma, metastatic tumor [especially breast, lung]); prolactin-secreting tumor is the most common pituitary neoplasm.
• Infiltrative diseases
• Granulomatous lesions (e.g., sarcoidosis, Hand-Schüller-Christian syndrome, histiocytosis X)
• Infection (e.g., TB, mycoses)
• Hemochromatosis
• Autoimmune inflammation
• Hemorrhage
• Pituitary necrosis secondary to postpartum hemorrhage (Sheehan's syndrome)
• Hemorrhage into pituitary tumor
• Infarction (e.g., sickle cell disease, cavernous sinus thrombosis)
• Miscellaneous
• Head trauma
• Internal carotid artery aneurysm
• Empty sella syndrome
• Idiopathic
• Isolated hormone deficiency (e.g., GH, ACTH, TSH, gonadotropin)
• Multiple hormone deficiency
• Iatrogenic (e.g., hypophysectomy, irradiation, section of stalk)
• Familial pituitary deficiency (deficient hormone production or production of abnormal hormone)
• Partial GH deficiency (some forms of "constitutional short stature" with delayed onset of adolescence)
• Hypothalamic disease
• End-organ resistance to GH (normal or increased serum GH with low somatomedin level)
• Laron dwarfs (somatomedin levels are often undetectable and fail to rise when GH is administered).

• Serum somatomedin C levels are 5-15% of normal in most hypopituitary dwarfs and 4-12 times normal in all active acromegaly patients.
• Endocrinologic findings: diagnosis is based on low serum level of target organ hormone and of the corresponding pituitary-stimulating hormone, e.g.,
• Hypogonadism
• Men: low sperm count, low serum testosterone, inappropriately low serum LH and FSH
• Women: low serum estradiol, inappropriately low serum LH and FSH
• Hypothyroidism
• Low serum T and FTI, inappropriately low serum thyrotropin
• Hypocorticalism:
• Low serum cortisol and ACTH
• Low serum GH unresponsive to provocative tests
• Low serum prolactin unresponsive to provocative tests. Usually occurs late in course of hypopituitarism except in Sheehan's syndrome, in which it may be the earliest manifestation. Rarely or never due to hypothalamic disease.
• See sections on secondary insufficiency of gonads, thyroid, adrenals. Only one (usually gonadal first) or all of these may be involved.

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• Dynamic tests are usually needed to detect partial deficiencies.
• See Diabetes Insipidus, Central.

Hypothalamus, Diseases

Due To

• Neoplasms (primary or metastatic cancer, craniopharyngioma) (most frequent cause)
• Inflammation (e.g., TB, encephalitis)
• Head trauma (e.g., basal skull fractures, gunshot wounds)
• Granulomas (e.g., histiocytosis X, sarcoidosis)
• Releasing-hormone deficiency, genetic or idiopathic
• Irradiation for childhood cancer

Manifestations

• Sexual abnormalities are the most frequent manifestations of hypothalamic disease.
• Precocious puberty
• Hypogonadism (frequently as part of Fröhlich's syndrome)
• Diabetes insipidus is a frequent but not an early manifestation of hypothalamic disease.
• Hypopituitarism-differentiate primary hypopituitarism from this secondary form of hypopituitarism by appropriate stimulation tests.

Multiple Endocrine Neoplasia (Men Syndrome)

MEN Type I (Wermer's Syndrome)

• (Triad of parathyroid, pancreatic islet cell, and anterior pituitary tumors)
• ○ Hyperparathyroidism (due to involvement of all four glands) in >88% of patients; is usual presenting feature; associated renal and bone disease are infrequent. 15% of cases of HPT have MEN; frequently multicentric. 10% of parathyroid tumor patients have relatives with MEN.
• ○ Pancreatic endocrine tumors in ~60% of patients; most are functional; usually multiple.
• Gastrinomas with Z-E syndrome occur in ~50% of cases and ~50% are malignant. 50% of cases of Z-E syndrome have MEN type I.
• Insulinomas (beta cells) in ~25% of MEN type I patients; usually benign; multiple foci are common.
• Glucagonomas (alpha cells) syndrome of distinctive rash, diabetes mellitus, anemia, weight loss.
• Vipomas occur less often.
• ○ Pituitary adenomas in 40-50% of cases
• ~25% are prolactinomas.
• ~15% are eosinophilic adenomas causing acromegaly.
• ~5% are basophilic adenomas causing Cushing's syndrome.
• ~10% are nonfunctional adenomas causing hypopituitarism due to space-occupying effect.
• ○ Tumors possible related to MEN type I
• Adrenal cortical adenomas or hyperplasia are incidental and nonfunctioning in ~10%, functioning in ~5% of cases. Adrenal medulla is not involved.
• Thyroid disease in ~20% of cases including benign and malignant tumors, colloid goiter, thyrotoxicosis, Hashimoto's disease.
• Uncommon lesions include carcinoids (~16%), schwannomas, multiple lipomas, gastric polyps, testicular tumors.

MEN Type II (or IIa) (Sipple's Syndrome)

• ○ Medullary thyroid carcinoma in >90% of cases is usually multicentric and preceded by C-cell hyperplasia (thereby differing from sporadic type). Produces calcitonin and sometimes ACTH or serotonin. Calcitonin response to IV pentagastrin stimulation

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has >90% sensitivity and specificity. 25% of these carcinomas occur as part of MEN type II. May be asymptomatic but lethal.

• ○ Pheochromocytoma in 10-50% of cases; usually bilateral, often multiple, and may be extra-adrenal. 10% of pheochromocytomas occur as part of MEN.
• ○ Hyperparathyroidism in ~20% of cases; due to hyperplasia in 84% and adenoma in 16%; occurs late in disease; may occur without medullary thyroid carcinoma.
• DNA analysis detected carriers of the gene before biochemical manifestations (100% sensitivity and specificity).30

MEN Type III (or IIb)

• (Features in common with MEN type II but is a separate genetic syndrome)
• ○ Medullary thyroid carcinoma in 75% of cases.
• ○ Pheochromocytoma in 33% of cases.
• Hyperparathyroidism is rare (<5% of cases).
• ○ Other lesions:
• Multiple mucosal gangliomas in >95% of cases appear early in life.
• Marfan syndrome habitus, hypertrophy of corneal nerves, ganglioneuromas of GI tract, characteristic retinal changes and facial appearance are frequent.
• ○ All first-order relatives of MEN patients should have appropriate serial testing.

Nonendocrine Neoplasms, Causing Endocrine Syndromes

• (Tumors secrete proteins, polypeptides, or glycoproteins that have hormonal activity.)
• Diagnosed by measuring arteriovenous gradient of hormone across tumor bed or between tumor and nontumor tissue; confirm by in vitro demonstration of hormone production by tumor cells and by resolution of endocrine syndrome after successful removal of tumor.
• Cushing's syndrome: increased blood ACTH level (>200 pg/mL), inability to suppress with high-dose DST (except in bronchial carcinoids), loss of diurnal variation of cortisol levels (usually >40 µg/dL). Therefore cannot be distinguished from excessive pituitary secretion of ACTH by use of DST. Typically malignant disease causing ectopic ACTH production has acute effects on adrenal glands manifested predominantly by excess mineralocorticoid production with hypokalemia and hypertension. May sometimes require selective venous catheterization to measure ACTH levels or in vitro hybridization assay to demonstrate ACTH-encoding messenger RNA to establish the diagnosis. Patients with lung cancer may have elevated ACTH levels without Cushing's syndrome.

Due To

• Bronchogenic oat cell carcinoma (causes ~50% of cases) and carcinoid
• Thymoma
• Hepatoma
• Carcinoma of ovary
• Also medullary carcinoma of thyroid, islet cell tumor of pancreas, etc. Hypercalcemia simulating HPT (see Humoral Hypercalcemia of Malignancy, and Table 13-7)
• Renal carcinoma
• Squamous cell and large-cell carcinoma of respiratory tract
• Carcinoma of breast (occurs in 15% of patients with bone metastases)
• Malignant lymphoma, myeloma, etc.
• Cancer of ovary, pancreas, etc.

• SIADH
• Especially with oat cell carcinoma of lung
• Hypoglycemia: serum insulin is low in presence of fasting hypoglycemia. Not associated with decreased serum phosphorus as in insulin-induced hypoglycemia.
• Bronchogenic carcinoma
• Carcinoma of adrenal cortex (6% of patients)

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• Hepatoma (23% of patients)
• Retroperitoneal fibrosarcoma (most frequently)
• Thyrotoxicosis: signs and symptoms are rare, but laboratory findings are present.
• Tumors of GI tract, hematopoietic tumors, pulmonary tumors, etc.
• Trophoblastic tumors in women
• Choriocarcinoma of testis
• Struma ovarii
• Precocious puberty in boys
• Hepatoma
• Acromegaly
• Pancreatic tumors producing GH or GH-releasing factor in presence of normal sella; increased GH not suppressed by glucose.
• Carcinoid.
• Erythrocytosis (due to erythropoietin production)
• Carcinoma of kidney, liver
• Fibromyoma of uterus
• Cerebellar hemangioblastoma
• See also Carcinoid Syndrome, Precocious Puberty, Syndrome of Inappropriate Secretion of Antidiuretic Hormone.

Pineal Tumors

• Boys-precocious puberty in 30% of patients
• Girls-delayed pubescence
• Diabetes insipidus occurs occasionally.

Pituitary Tumors

• Findings due to increased production of hormones or effect of growing mass.
• Most common tumors are
• Prolactin-secreting tumors comprise ~30% of all pituitary tumors (see Prolactinomas)
• GH-secreting tumors (see Acromegaly and Gigantism)
• ACTH-secreting tumors (see Cushing's Syndrome)
• Nonfunctioning adenomas, which may produce findings of intracranial mass, especially with visual changes, and hypopituitarism (sometimes with impaired hypothalamic function)
• Microadenomas (<10 mm in size) may be present in 10-20% of the population by autopsy and radiographic studies ("incidentaloma") but tumors >10 mm in size are quite rare.

Polydipsia, Psychogenic

• (Excessive intake of water causes loss of medullary sodium and urea to renal venous blood and abnormally reduced tonicity of renal medulla.)
• See Table 13-26.
• ○ Should be suspected when large volumes of very dilute urine occur with plasma osmolality that is only slightly decreased or low normal.
• Test dose of vasopressin often shows failure to concentrate urine, simulating nephrogenic diabetes insipidus. However, the test is normal when performed after restoration of normal hypertonicity of renal medulla by a period of high sodium and low water intake.
• Fluid deprivation test is least reliable in differentiating this from partial central diabetes insipidus; e.g., some increase in urine osmolality after dehydration with an inconclusive (~10%) further increase after vasopressin may be due to either condition.

Polyglandular Syndromes, Autoimmune

Type I

• Requires two or more of the following: hypoparathyroidism, Addison's disease, chronic mucocutaneous candidiasis (all three are present in approximately one-third

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of patients). Patient may also have associated immune disorders, e.g., autoimmune hypothyroidism. Gonadal failure and chronic hepatitis may also occur.

Type II (Schmidt's Syndrome)

• Autoimmune thyroiditis or insulin-dependent diabetes (15% of all patients with insulin-dependent diabetes mellitus have type II) with Addison's disease. Interval between onset of endocrinopathies may be up to 20 yrs. Gonadal failure may sometimes occur.
• (For comparison of types I and II, see Table 13-28.)

Type III

Autoimmune thyroid disease with two other autoimmune disorders, including insulin-dependent diabetes mellitus, PA, or a non-endocrine-organ-specific autoimmune disorder (e.g., myasthenia gravis) but without Addison's disease.

Prolactinomas

Serum Prolactin Reference Values

• Normal <25 ng/mL in females; lower in males and children.
• Gradual increase from birth until adolescence
• 13- to 15-yr-old boys: 2.5× adult levels
• 13- to 15-yr-old girls: 3× adult levels
• Serum samples should be collected under basal conditions with minimal stress and by pooling three blood samples collected at 20-min intervals for one assay; all drugs should be discontinued for at least 2 wks before testing.

Interpretation

• 40-85 ng/mL: seen in craniopharyngioma, hypothyroidism, effect of drugs
• 50 ng/mL: 25% chance of a pituitary tumor

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• 100 ng/mL: 50% chance of a pituitary tumor
• <200 ng/mL with a macroadenoma, particularly with extrasellar extension, is most likely due to compression of pituitary stalk rather than prolactinoma.
• 200-300 ng/mL: nearly 100% chance of a pituitary tumor; >200 ng/mL may indicate a macroadenoma rather than microadenoma and tumor usually is visible on CT or MRI, but CT or MRI is normal in ≤ 20% of microadenomas.
• High levels may be seen with simultaneous multiple additive factors that usually cause lesser increases (e.g., chronic renal failure plus use of methyldopa)
• Immediate postoperative level of <7.0 ng/mL indicates long-term cure but higher levels are associated with recurrence.
• Repeated serum levels in late morning or early afternoon that are increased 3-5× normal in men or nonlactating women are usually considered diagnostic of pituitary adenoma or rarely of hypothalamic disease or pituitary stalk section or hypothyroidism. One elevated level is not adequate for diagnosis. Level normally increases sharply during sleep; higher in morning than afternoon.

Increased Serum Prolactin In

• Amenorrhea/galactorrhea
• 10-25% of women with galactorrhea and normal menses
• 10-15% of women with amenorrhea without galactorrhea
• 75% of women with both galactorrhea and amenorrhea/oligomenorrhea
• Causes 15-30% of cases of amenorrhea in young women
• Pituitary lesions (e.g., prolactinoma, section of pituitary stalk, empty sella syndrome, 20-40% of patients with acromegaly, up to 80% of patients with chromophobe adenomas)
• Hypothalamic lesions (e.g., sarcoidosis, eosinophilic granuloma, histiocytosis X, TB, glioma, craniopharyngioma)
• Other endocrine diseases
• ~20% of cases of hypothyroidism (second most common cause of hyperprolactinemia). Therefore serum TSH and T should always be measured
• Addison's disease
• Polycystic ovaries
• Glucocorticoid excess-normal or moderately elevated prolactin
• Ectopic production of prolactin (e.g., bronchogenic carcinoma, renal cell carcinoma, ovarian teratomas, acute myeloid leukemia)
• Children with sexual precocity-may be increased into pubertal range
• Neurogenic causes (e.g., nursing and breast stimulation, spinal cord lesions, chest wall lesions such as herpes zoster)
• Stress (e.g., surgery, hypoglycemia, vigorous exercise)
• Pregnancy (increases to 8-20× normal by delivery, returns to normal in 2-4 wks postpartum unless nursing occurs)
• Lactation
• Chronic renal failure (20-40% of cases; becomes normal after successful renal transplant but not hemodialysis)
• Liver failure (due to decreased prolactin clearance)
• Idiopathic causes (some probably represent early cases of microadenoma too small to be detected by CAT scan)

Interferences

• Drugs-most common cause; usually subsides a few weeks after cessation of using drug; these elevations are usually <100 ng/mL
• Neuroleptics (e.g., phenothiazines, thioxanthenes, butyrophenones)
• Antipsychotic drugs (e.g., Compazine, chlorpromazine [Thorazine], trifluoperazine hydrochloride [Stelazine], thioridazine hydrochloride (Mellaril), haloperidol lactate [Haldol])
• Dopamine antagonists (e.g., metoclopramide, sulpiride)
• Opiates (morphine, methadone)
• Reserpine
• Alpha-methyldopa (Aldomet)
• Estrogens and oral contraceptives
• TRH
• Amphetamines
• Isoniazid

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Serum Prolactin May Be Decreased In

• Hypopituitarism
• Postpartum pituitary necrosis (Sheehan's syndrome)
• Idiopathic hypogonadotropic hypogonadism
• Use of certain drugs
• Dopamine agonists
• Ergot derivatives (bromocriptine mesylate, lergotrile mesylate, lisuride hydrogen maleate)
• Levodopa, apomorphine, clonidine

Interpretation

• Normal value in child with growth retardation virtually rules out hypopituitarism but a low value is not diagnostic. Single blood value may be more reliable than multiple measurements of GH in diagnosis of active acromegaly.
• TRH stimulation of patients with increased prolactin not due to pituitary tumors usually doubles serum prolactin level to peak of >12 ng/mL in 15-30 mins, but most patients with prolactinomas do not respond to TRH stimulation (response <2× baseline level). Enhanced responsiveness in hypothyroidism and blunted prolactin rise in chronic renal failure. Unresponsiveness to TRH (<2× baseline level) also occurs in panhypopituitarism. Measurement of multiple basal prolactin levels has replaced stimulation tests for diagnosis of prolactinoma.
• Microscopic examination of breast discharge shows numerous fat globules; if not seen, rule out intraductal breast carcinoma or infection.
• Normal or decreased serum FSH, LH, and testosterone may occur in men.
• Women may also present with hirsutism, infertility. Men may present with decreased libido, impotence, oligospermia, low serum testosterone levels, and sometimes galactorrhea.
• Hypothyroidism
• Acute fasting and chronic protein-calorie deprivation (when GH often rises)

Syndrome of Inappropriate Secretion of Antidiuretic Hormone (Siadh)

(Syndrome of continuing release of vasopressin in presence of low plasma osmolality; kidney responds normally to arginine vasopressin.)

Due To

• CNS disease of all types (e.g., neoplastic, degenerative, infective, traumatic, vascular, psychogenic)
• Advanced endocrinopathies (e.g., myxedema, ACTH deficiency, adrenal insufficiency)
• Neoplasms (most commonly oat cell carcinoma of lung; adenocarcinoma of lung, carcinoma of pancreas, carcinoma of duodenum, lymphoma), some of which show ectopic production of ADH
• Pulmonary diseases (e.g., cancer, pulmonary emboli, TB, pneumonia, chronic infections, lung abscess, aspergillosis)
• Miscellaneous (e.g., acute intermittent porphyria, postoperative state)
• Idiopathic causes
• Various drugs
• Oral hypoglycemic agents (chlorpropamide, tolbutamide, phenformin, metformin)
• Antineoplastic agents (vincristine, cyclophosphamide)
• Diuretics (chlorothiazide)
• Sedatives, analgesics (morphine, barbiturates, acetaminophen)
• Psychotropic drugs (amitriptyline, phenothiazines)
• Miscellaneous (clofibrate, isoproterenol, nicotine)
• Cause should be established because some causes are curable with resolution of SIADH. Cortisol deficiency and hypothyroidism should always be excluded
• Dilutional hyponatremia with appropriately decreased osmolality (usually <280 mOsm/kg) when urine is not at maximum dilution; this is basis for diagnosis in

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patient with no evidence of cardiac, liver, kidney, adrenal, pituitary, or thyroid disease, or hypovolemia and not on drug therapy (especially diuretics).

• Increased urine sodium (>20 mmol/L; >30 mmol/day) with inappropriately high urine osmolality (>500 mOsm/kg) is essential for diagnosis because it excludes hypovolemia as the cause of hyponatremia (in absence of abnormal renal function or causative drugs)
• Increased urine osmolality higher than serum osmolality
• Normal serum potassium, CO , BUN, and creatinine
• Decreased serum chloride
• Decreased AG
• Decreased uric acid (due to dilution)
• Increase in plasma vasopressin that is inappropriate for the degree of plasma osmolality is not helpful in diagnosis because most causes of true hyponatremia are associated with detectable or increased vasopressin. (See Arginine Vasopressin.)
• Clinical and biochemical response to fluid restriction but not to administration of isotonic or hypertonic saline

Thyroid-Stimulating Hormone (Tsh)-Secreting Pituitary Adenomas

• (Rare type of adenoma that causes hyperthyroidism)
• Laboratory findings of hyperthyroidism except serum TSH is increased and does not increase in response to TRH stimulation or does not decrease in response to suppressive doses of thyroid hormone.
• Increased molar ratio of alpha subunit of TSH to whole TSH.
• ○ Secretion of other hormones (e.g., prolactin, GH) occurs in about one-third of these cases.

REFERENCES

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3. Data from National Diabetes Data Group, 1978.

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21. Peplinski GR, Norton JA. The predictive value of diagnostic tests for pheochromocytoma. Surgery

22. Eisenhofer GE, et al. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia Type 2. N Engl J Med

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Footnotes

TSH injection causes increase of ≥50% of RAIU in normal persons.

TSH injection does not cause a normal increase of ≥50% of RAIU.

Urinary iodine >2000 µg/24 hrs.